A number of tumor necrosis factor receptor proteins (“TNFR proteins”) and proteins homologous thereto have been isolated in recent years. They have many potent biological effects and aberrant activity of these proteins has been implicated in a number of disease states.
One such TNFR homologue, reported in July, 1998 (Gentz et al., WO 98/30694), binds the protein FAS Ligand and thereby inhibits the activation of another TNFR homologue, FAS, by FAS Ligand (U.S. Provisional Applications Ser. Nos. 60/112,577, 60/112,933, and 60/113,407, filed Dec. 17, 18 and 22, 1998, respectively; the entire teachings of these applications are incorporated herein by reference).
This new protein is referred to herein as “FAS Ligand Inhibitory Protein” or “FLINT”.
Over activation of FAS by FAS Ligand has been implicated in a number of pathological conditions, including runaway apoptosis (Kondo et al., Nature Medicine 3(4):409-413 (1997) and Galle et al., J. Exp. Med. 182:1223-1230 (1995)) and inflammatory disease resulting from neutrophil activation (Miwa et al.,. Nature Medicine 4:1287 (1998)).
“Runaway apoptosis” is a level of apoptosis greater than normal, or apoptosis occurring at an inappropriate time. Pathological conditions caused by runaway apoptosis include, organ failure, for example, in the liver, kidneys and pancreas. Inflammatory diseases associated with excessive neutrophil activation include, but are not limited to, sepsis, ARDS, SIRS and MODS.
Compounds such as FLINT which inhibit the binding of FAS to FAS Ligand, or LIGHT to LTβR and/or TR2/HVEM receptors can be used to treat or prevent diseases or conditions that are mechanistically-linked to these binding interactions. However, the potential of FLINT as a useful therapeutic is dependent, at least in part, on the development of analogs with improved pharmacological properties (e.g., greater potency, longer in vivo half-lives and greater affinity for FAS Ligand) and/or improved pharmaceutical properties (e.g., decreased aggregation and surface absorption properties and increased solubility and ease of formulation).